Our goal is to determine whether it is possible to tip the ecological balance in dental plaque in favor of oral microorganisms associated with health, rather than with disease. In pursuit of this goal, we will establish a functional genomics map of the genes and proteins involved in the oxidative stress response mechanisms of Streptococcus mutans, a causative agent of dental caries in humans. S. mutans relies on its stress-response systems to out-compete organisms such as Streptococcus sanguinis or S. gordonii, bacteria that are associated with oral health. The map of S. mutans oxidative stress responses will provide novel, and organism-specific, targets for the development of therapeutic agents to reduce or prevent dental caries. In the proposed project, we will use high-throughput proteomic and transcriptomic approaches to identify genes associated with the S. mutans oxidative stress response. In Aim 1 of the project, we will use proteomics to identify proteins associated with the S. mutans oxidative stress response. In Aim 2, we will use a complementary transcriptomic approach to establish the number of S. mutans genomic transcripts associated with the oxidative stress response. In Aim 3, we will use an established collection of genetically barcoded deletion mutant strains of S. mutans, created by our laboratory, to assign mutant strains to the proteins and transcripts identified in Aims 1 and 2. This sub-library of mutant strains will be co-cultured with S. gordonii to determine the contribution of each gene in the sub-library to the ability of S. mutans to compete with S. gordonii. In Aim 4, we will use the sub-library of mutant strains, identified in Aim 3, in the rat model of oral microbial infection, to determine the contribution of each oxidative stress gene to the ability of S. mutans to infect rats We will also use the deletion mutant sub-library to test sensitivity to compounds known to affect the ability of S. mutans to grow. In this way, we will identify metabolic pathways responsive to oxidative stress. Our long-term goal is to identify new, and possibly probiotic, mechanisms for reducing dental disease in humans.